This invention relates to a method for the treatment of preeclampsia and of preterm labor with the combination of a progestational agent and a nitric oxide synthase substrate, a nitric oxide donor or both, alone or in further combination with one or more of a cyclooxygenase inhibitor, a PGI2-mimetic, a thromboxane (TXA2) inhibitor, A compound possessing TXA2-agonistic and TXA2-inhibiting properties, a compound possessing TXA2 antagonistic and PGI2-memetic activities, and a TXA2 antagonist, and to pharmaceutical compositions comprising such a combination.
Preeclampsia, toxemia or eclampsia of pregnancy can be a significant health problem during pregnancy and they are the leading causes of fetal growth retardation, fetal mortality and morbidity, premature birth and maternal mortality. The etiology of the disease is largely unknown and effective therapy is not available. Preeclampsia of pregnancy is characterized by a triad of hypertension, pathological edema and proteinuria. This disease affects 6 to 10% of all pregnancies.
Recently, nitric oxide has been shown to be endothelium derived relaxing factor (EDRF) from the endothelium of blood vessels. Nitric oxide is considered to be a major mediator in the control of vascular reactivity. Nitric oxide is synthesized from L-arginine by nitric oxide synthase located in endothelial cells. Nitric Oxide can also be generated by application of various nitric oxide donors such as sodium nitroprusside, nitroglycerin, glyceryl trinitrite, SIN-1, isosorbid mononitrite, isosorbid dinitrite, etc.
Treatment of pregnant rats with nitric oxide synthase inhibitors, which are analogues of L-arginine (such as L-NAME, NG-nitro-L-arginine methyl ester) results in elevated blood pressure, fetal retarded growth and proteinuria. Thus, inhibition of nitric oxide synthesis produces conditions and symptoms identical to preeclampsia of pregnancy and establishes that preeclampsia is the direct result of the decrease in nitric oxide synthesis and/or a change in the regulation of vascular tone. These conditions give rise to increased blood pressure, decreased blood flow to the fetus, retarded fetal development and proteinuria. Agents which raise nitric oxide levels therefore are useful in the treatment of preeclampsia of pregnancy. Since nitric oxide donors also reduce contractility of the uterus during pregnancy, nitric oxide donors are also useful for use in preterm labor.
The nitric oxide effects on smooth muscle depend upon the activation of guanylate cyclase and generation of cGMP to produce relaxation and this step is progesterone dependent. Thus, combinations of nitric oxide donors with progesterone are particularly efficacious for the treatment of preeclampsia and of preterm labor.
EP 0 441 119 A2 discloses the use of L-arginine in the treatment of hypertension and other vascular disorders. It suggests that the mechanism by which L-arginine is effective for this purpose is because it may be the physiological precursor of “the most powerful endothelial-derived releasing factor, nitric oxide.” The use of L-arginine in combination with other pharmaceutically active agents is not discussed in this publication.